Understanding molecular changes in progression of head and neck squamous cell carcinoma (HNSCC) is essential for predicting clinical outcome and for developing effective therapies for treating the disease. Plakophilin-1 is a member of the Armadillo (Arm) protein family that is a structural component of the cell-cell adhesion junction known as the desmosome. In addition, plakophilin-1 is found in the nucleus, where its function is unknown. A well-studied member of the Arm family, ?-catenin, normally associates at the plasma membrane with the adherens cell-cell adhesion complex but also is found in the nucleus where it is a transcriptional regulator in the Wnt signaling pathway and plays a critical role in colon cancer. Data presented in this proposal show that not only is plakophilin-1 protein expression reduced in HNSCC, reducing plakophilin-1 expression in cell lines leads to increased cell motility in vitro. The central hypothesis for this project is that plakophilin-1, similar to ?-catenin, plays roles in both cell-cell adhesion and gene expression and that a shift in these cellular events plays a critical role in the malignant progression of HNSCC. The goal for the proposed work is to define the nuclear role for plakophilin-1 in HNSCC by showing that loss of plakophilin-1 expression alters the expression of genes relevant to tumor progression. The specific aims are (1) to determine the mechanisms of plakophilin-1 translocation to the nucleus, (2) to determine the nuclear function of the plakophilin-1/TLS complex, and (3) to determine the role of plakophilin-1 target genes in HNSCC progression. This work will be greatly aided by two tools already developed for the project: a highly specific monoclonal antibody to plakophilin-1 and an activatable form of plakophilin-1 that can be exogenously expressed in cells. Defining the nuclear function of plakophilin-1 will lay the ground work for identifying new prognostic markers for HNSCC and also potential targets for novel therapeutic strategies for treating the disease.